Alterations of composition and pressure of respiratory gases have allowed extension of manned activity to extreme altitude, to the lunar surface, and to deep undersea regions. Alterations of respiratory gases also can disrupt physiological balance, produce lasting harm, or induce lethal effects. They can sustain life in disease states. This program concerns each of the circumstances cited in which natural or other respiratory gases effect functional states. The investigations of metabolically active and inert respiratory gases were all performed by dose-response methods to elaborate limits of tolerance to increasing partial pressures or density. Adaptations and deteriorations of sensory, cognitive, neuromuscular, pulmonary, respiratory, cardiovascular and exercise functions are determined to provide bases both for elucidating mechanisms of gas effects and predicting the consequences of complex exposures. Investigation of inert gas exchange in organs and tissues provided the basis for systems of decompression and aids understanding of biophysical factors in bubble formation and resolution. A major area of investigation concerns oxygenation and oxygen tolerance. Within the narrow range of oxygen pressures tolerated by living cells, the processes of cellular oxidation and energy metabolism depend upon effective delivery of oxygen to the metabolic site and the balance of oxidant-antioxidant processes. Inadequate tissue oxygenation limits the ultimate oxidation process. Excessive oxygenation, as in therapeutic or other use of high oxygen pressures, disrupts the enzyme activity upon which oxidation itself depends. Both oxygenation and oxidation processes, and even the poisoning by hypoxia, are affected by exposures to extreme alterations of carbon dioxide, inert gases, and certain respired toxic gases. In addition to its relation to abnormal environments, this program of interrelated studies is therefore concerned with respiratory, cardiovascular, gas transport and metabolic influences of both low and high oxygen pressures in disease and the interrelationships of respiratory gas effects upon vital functions.